This proposal focuses on research in the area of cycloaddition reactions and methods, with emphasis on the total synthesis of stereochemically complex natural products. It is expected that this methodology will facilitate synthesis of analogs and SAR studies of biologically active natural products, and other drug- like small molecules. Specific goals are: (I) Synthetic Applications of Siloxacyclopentene-Constrained Trienes. New methodology involving siloxacyclopentene-constrained trienes will be applied to the total syntheses of FR182877, an antimitotic agent with significant cytotoxicity against a broad range of cancer cell lines, and of hirsutellones A-C, a group of alkaloids with anti-mycobacterial activity. The siloxacyclopentene constraint unit will be used to control the face selectivity of the diene and dienophile units in the proposed Diels-Alder reactions. (II) Total Synthesis of Integramycin. Integramycin is a structurally novel inhibitor of HIV-1 integrase, an enzyme target that is viewed as an important new target for HIV/AIDS therapy. The highly convergent total synthesis of integramycin initiated in the previous grant period will be completed. Based on the expectation that the 5-hydroxy-4-acyl tetramic substructure is the active pharmacophore unit of the natural product, analogs will be synthesized with a variety of groups replacing the structurally complex octahydronaphthalene unit, with the goal of developing structurally simpler HIV-1 integrase inhibitors. (III) Total Synthesis of Sporolides A and B. Sporolides A and B are structurally novel marine natural products. While no biological activity has yet been ascribed to the sporolides, genomic evidence suggests that the sporolides are generated by a biosynthesis involving an enediyne intermediate. In view of the potent biological properties of enediyne antibiotics, a synthesis of sporolides A and B will be developed that proceeds by way of enediyne intermediates. The chemistry and biology of the enediyne intermediates will be probed if these compounds are sufficiently stable. (IV) Synthetic Studies of Phosphine-Mediated C-C Bond Forming Reactions. The trialkylphosphine-mediated tandem vinylogous Morita-Baylis-Hillman and aldol reactions of 1,5-diketones will be applied to the synthesis of a calcitriol precursor, and to the synthesis of gymnasterone B and gymnasterol, two novel cytotoxic steroid derivatives. Gymnasterol displays potent activity against insulin- like growth factor (IGF)-1 dependent human breast cancer cells. The IGFs play a critical role in cancer progression and selective inhibition of IGF signal transduction is a new strategy for the development of novel anticancer agents. PUBLIC HEALTH RELEVANCE: The relevance of this project to public health is that new synthetic methodology and strategies will be developed that will greatly simplify the synthesis of biologically active natural products such as FR182877, hirsutellones A-C, integramycin, sporolides A and B, gymnasterone B and gymnasterol. The new synthetic methodology and synthetic strategies developed in this research will facilitate structure activity relationship studies of many natural and unnatural products in research worldwide.